Rescue of radiation-induced salivary gland dysfunction by Akt

描述(申请人提供)：唾液腺是头部和颈部照射后异常细胞凋亡的部位，导致严重的腺体功能障碍。在治疗期间，这些患者暴露在多轮放射治疗中，这对正常的唾液腺造成了显著的损害。转基因小鼠已经被创造出来，表达一种结构性激活的Akt1(MYR-Akt1)，它显著降低了暴露于靶向头颈部辐射后唾液腺的细胞凋亡水平。这项研究的初步结果表明，MYR-Akt1转基因小鼠在接受单次治疗剂量的电离辐射后，也恢复了唾液流量，提供了细胞凋亡和唾液腺功能障碍之间的相关性。虽然这些结果非常有希望，但接受治疗性放射治疗的头颈部癌症患者会接受多剂量的辐射。这项建议的总体目标是确定Akt在分次剂量辐射后维持唾液腺功能和动态平衡的能力。作为翻译这些研究的一种手段，我们之前已经表明，与其他生长因子相比，IGF1在唾液腺泡细胞中诱导强大的Akt激活(1)。这项建议的长期目标是评估在头颈部照射前对唾液腺进行IGF1治疗是否可以原位激活Akt，并影响唾液腺功能障碍和口干的临床治疗。我们推测Akt通过增强DNA修复通路和抑制凋亡通路，在放射治疗后改善唾液功能中发挥关键作用。具体目标1将评估Akt在头颈部分次剂量照射后维持唾液腺功能的能力。特定目的2将研究Akt在辐射诱导的唾液腺功能障碍中调节DNA修复中的作用。这些研究的一个独特和创新的优势是使用了表达Akt1基因活性突变的转基因小鼠。这种小鼠模型和来自这些小鼠的原代唾液腺泡细胞培养允许转基因小鼠与对照小鼠在靶向头颈部动物照射中进行直接比较，并能够将原代培养的初步结果与体内组织学或生化变化的检查联系起来。这项建议还侧重于唾液腺功能障碍和治疗辐射敏感性的机制分析，以便将这些结果应用于翻译应用研究。这些研究将显著提高我们对压力环境下唾液腺生物学的理解，而患者插入唾液腺导管的独特能力为临床应用提供了乐观的前景。 放射是大多数头颈部癌症患者的常见治疗方法，大多数患者会导致唾液流失。由此导致的唾液腺活动不足会导致显著的副作用，从而降低抗癌治疗的有效性，并降低这些患者的生活质量。这项建议的总体目标是确定细胞死亡在辐射后唾液腺功能丧失中所起的作用，并评估是否可以在头颈部照射之前使用防止细胞死亡的物质，以防止唾液腺功能障碍和口干症。

DESCRIPTION (provided by applicant): Salivary glands are the site of aberrant apoptosis following head and neck irradiation resulting in severe glandular dysfunction. During therapy, these patients are exposed to multiple rounds of radiation treatment which takes a significant toll on the normal salivary gland. Transgenic mice have been created expressing a constitutively activated Akt1 (myr-Akt1) which significantly reduces the level of apoptosis in the salivary glands following exposure to targeted head and neck radiation. Preliminary results presented in this proposal have indicated the myr-Akt1 transgenic mice also rescue salivary flow rates following a single therapeutic dose of ionizing radiation providing a correlation between apoptosis and salivary gland dysfunction. While these results are very promising, patients undergoing therapeutic radiation for head and neck cancer receive multiple doses of radiation. The general goal of this proposal is to define the ability of Akt to maintain salivary gland function and homeostasis following fractionated doses of radiation. As a means to translate these studies, we have previously shown that IGF1 induces robust Akt activation in salivary acinar cells when compared to other growth factors (1). The long-term goal of this proposal is to evaluate whether IGF1 treatment of salivary glands prior to head and neck irradiation could activate Akt in situ and impact clinical therapeutics for salivary gland dysfunction and xeriostomia. We hypothesize that Akt plays a pivotal role in improved salivary function following therapeutic radiation by enhancement of DNA repair pathways and suppression of apoptotic pathways. Specific Aim 1 will evaluate the ability of Akt to maintain salivary gland function following fractionated doses of head and neck radiation. Specific Aim 2 will investigate the role of Akt in regulating DNA repair in ?-irradiation-induced salivary gland dysfunction. A unique and innovative strength of these studies is the use of transgenic mice that express a constitutively active mutant of Akt1. This mouse model and primary salivary acinar cell cultures from these mice allow the direct comparison of transgenic mice with control mice in targeted head and neck animal irradiation and the ability to relate in vitro preliminary results from primary cultures with in vivo examination of histological or biochemical changes. This proposal also focuses on a mechanistic analysis of salivary gland dysfunction and sensitivity to therapeutic radiation in order to apply these results towards translation application studies. These studies will significantly improve our understanding of salivary gland biology in stressed environments and the unique ability to cannulate salivary gland ducts in patients provides the optimism for clinical application. Radiation is a common treatment in most head and neck cancer cases and results in the loss of saliva in most patients. The resulting lack of salivary gland activity results in significant side effects, which diminish the effectiveness of anti-cancer therapies, and decreases the quality of life for these patients. The general goal of this proposal is to define the role cell death serves in loss of salivary gland function following exposure to radiation and evaluate whether substances that prevent cell death could be used prior to head and neck irradiation in order to prevent salivary gland dysfunction and xerostomia.